Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer

Cancer Cell. 2013 Mar 18;23(3):316-31. doi: 10.1016/j.ccr.2013.01.022. Epub 2013 Feb 28.

Abstract

The epithelial-mesenchymal transition (EMT) enhances cancer invasiveness and confers tumor cells with cancer stem cell (CSC)-like characteristics. We show that the Snail-G9a-Dnmt1 complex, which is critical for E-cadherin promoter silencing, is also required for the promoter methylation of fructose-1,6-biphosphatase (FBP1) in basal-like breast cancer (BLBC). Loss of FBP1 induces glycolysis and results in increased glucose uptake, macromolecule biosynthesis, formation of tetrameric PKM2, and maintenance of ATP production under hypoxia. Loss of FBP1 also inhibits oxygen consumption and reactive oxygen species production by suppressing mitochondrial complex I activity; this metabolic reprogramming results in an increased CSC-like property and tumorigenicity by enhancing the interaction of β-catenin with T-cell factor. Our study indicates that the loss of FBP1 is a critical oncogenic event in EMT and BLBC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Carrier Proteins / biosynthesis
  • Cell Hypoxia
  • Cell Line, Tumor
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA Methylation
  • Electron Transport Complex I / metabolism
  • Epithelial-Mesenchymal Transition*
  • Female
  • Fructose-Bisphosphatase / genetics
  • Fructose-Bisphosphatase / metabolism*
  • Glucose / metabolism
  • Glycolysis / genetics
  • Histocompatibility Antigens
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Membrane Proteins / biosynthesis
  • Mice
  • Mice, Inbred ICR
  • Mice, SCID
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / metabolism*
  • Oxidative Phosphorylation
  • Oxygen Consumption / genetics
  • Promoter Regions, Genetic
  • Reactive Oxygen Species / metabolism
  • Snail Family Transcription Factors
  • TCF Transcription Factors / metabolism
  • Thyroid Hormones / biosynthesis
  • Transcription Factors / metabolism*
  • beta Catenin / metabolism

Substances

  • Carrier Proteins
  • Histocompatibility Antigens
  • Membrane Proteins
  • Reactive Oxygen Species
  • Snail Family Transcription Factors
  • TCF Transcription Factors
  • Thyroid Hormones
  • Transcription Factors
  • beta Catenin
  • thyroid hormone-binding proteins
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases
  • DNMT1 protein, human
  • Dnmt1 protein, mouse
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase
  • Fructose-Bisphosphatase
  • Electron Transport Complex I
  • Glucose

Associated data

  • GEO/GSE41158